To date, cancer remains the single most common cause of morbidity and mortality of humans. The majority of cancer patients die as a result of metastasis of the primary tumor to tissues other than the primary tumor site, and in particular, to bone tissue. Patients with bone metastases have a poor prognosis which accounts for a large proportion of deaths resulting from cancer metastases. For example, in virtually 100% of patients with advanced disease, prostate cancer metastasizes to osseous sites and kills over 40,000 people per year.
Because the mechanisms which contribute to bone metastasis are poorly understood, rational drug design to reduce, prevent, or inhibit metastasis to bone has not been possible. It has been hypothesized that the bone environment provides a favorable growth advantage for cancer cells which non-selectively seed the bone marrow from the bloodstream (Galasko (1981) Clin. Orthop. 155:269-285; Paget (1989) Lancet 1:571-573; Galasko (1981) Bone Mestastes, Weiss and Gilbert, eds., G. K. Hall Medical Publisher, pp. 49-63; Jacobs (1983) Urology 21:337-344; Body (1992) Bone 13:S57-S62;). An alternative, but not mutually exclusive, hypothesis suggests that cancer cells preferentially bind to bone marrow endothelial cells as compared to endothelial cells lining the blood vessels of other organs. Once a tumor cell has successfully arrested in bone tissue, there are a myriad of growth factors and cytokines available that stimulate the cells to proliferate. Bone marrow contains many growth factors (e.g., transforming growth factor-beta, Insulin-like growth factors I and II, basic fibroblast growth factor, platelet-derived growth factor, interleukins-1and 6, and transferrin (Zetter et al. (1992) in ProstateCancer and Bone Metastasis, J. P. Karr and H Yamanaka, eds., Plenum Press, New York, N.Y.; Bautista et al. (1990) Metabolism 39:96-100; Hauschka et al. (1986) J. Biol. Chem. 261:12665-12674; Littlewood et al. (1991) Endocrinology 129:1513-1520;) which are normally involved in hemopoiesis and which have been shown to be powerful mitogens for a variety of cell lines. Indeed, cells from prostatic carcinoma appear to grow more rapidly in bone marrow than in the primary tumor (Zetter et al. (1992) in ProstateCancer and Bone Metastasis, J. P. Karr and H Yamanaka, eds., Plenum Press, New York, N.Y.).
The study of cancer metastasis to bone, and consequently, a rational approach to anti-metastatic drug design, have been hampered by the shortage of appropriate in vitro and in vivo models of tumor metastasis. To date, the principal prior art model for cancer metastasis to bone relies on injecting cancer cells into an animal, and observing seeding of cancer cells into bone tissue (see, e.g., (Haq et al. (1992) Cancer Res. 52:4613-4619). However, this in vivo model suffers from lack of reproducibility in seeding, as well as paucity of evidence on whether seeding was selective or non-selective (Haq et al. (1992) Cancer Res. 52:4613-4619).
Thus, there remains a need for a model for the study of tumor metastasis to bone.